| Combinations of paroxetine and 2-(r)-(4-fluoro-2-methyl-phenyl)-4-(s)-((8as)-6-oxo-hexahydro-pyrrolo'1,2-a!-pyrazin-2-yl)-piperidine-1-carboxylicacid'1-(r)-(3,5-bis-trifluoromethyl-phenyl)- -> Monitor Keywords |
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Combinations of paroxetine and 2-(r)-(4-fluoro-2-methyl-phenyl)-4-(s)-((8as)-6-oxo-hexahydro-pyrrolo'1,2-a!-pyrazin-2-yl)-piperidine-1-carboxylicacid'1-(r)-(3,5-bis-trifluoromethyl-phenyl)-Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of Two Nitrogens And Four Carbon Atoms (e.g., Pyridazines, Etc.), 1,4-diazine As One Of The CyclosCombinations of paroxetine and 2-(r)-(4-fluoro-2-methyl-phenyl)-4-(s)-((8as)-6-oxo-hexahydro-pyrrolo'1,2-a!-pyrazin-2-yl)-piperidine-1-carboxylicacid'1-(r)-(3,5-bis-trifluoromethyl-phenyl)- description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060287325, Combinations of paroxetine and 2-(r)-(4-fluoro-2-methyl-phenyl)-4-(s)-((8as)-6-oxo-hexahydro-pyrrolo'1,2-a!-pyrazin-2-yl)-piperidine-1-carboxylicacid'1-(r)-(3,5-bis-trifluoromethyl-phenyl)-. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present invention relates to therapeutic combinations comprising paroxetine or physiologically acceptable salts or solvates thereof and 2-(R-(4Fluoro-2-methyl-phenyl)-4-(S)((8aS)-6-oxo-hexahydro-pyrrolo[1,2-a]- -pyrazin-2-yl)-piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide or pharmaceutically acceptable salts or solvates thereof, to pharmaceutical compositions containing said combinations and their use in the treatment of depression and/or anxiety. [0002] Paroxetine ((-) trans-4-(4'-fluorophenyl)3-(3'-4'-methylenedioxyphenoxymethyl)piperidine) and its salts are commercially available and approved for use in humans for treatment and prophylaxis of, inter alia, anxiety, depression, obsessive compulsive disorder (OCD), premenstrual dysphroic disorder(PMDD) and panic disorders. [0003] 2-(R-(4Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro-pyrrolo- [1,2-a]-pyrazin-2-yl)-piperidine-1-carboxylic acid [1-(R-(3,5bis-trifluoromethyl-phenyl)ethyl]-methylamide or pharmaceutically acceptable salts or solvates thereof, which is described in WO 03/066635, is a NK.sub.1 receptor antagonist. [0004] NK.sub.1 receptor antagonists are known to be useful in the treatment of anxiety and depression, chemotherapy-induced nausea and vomiting and post-operative nausea and vomiting. Preclinical data suggest that NK.sub.1 receptor antagonists may be useful in a variety of other disorders including pain, inflammatory diseases, allergic disorders, CNS disorders, skin disorders, cough and gastrointestinal disorders. [0005] U.S. Pat. No. 6,117,855 describes the use of a CNS-penetrant NK, receptor antagonist together with antidepressant or anti-anxiety drug for the manufacture of a medicament for the treatment or prevention of depression and/or anxiety. [0006] There is however no specific disclosure of such combinations with paroxetine. [0007] WO 03/066635 broadly teaches that the NK.sub.1 receptor antagonists described therein may be administered in combination with a SSRI agent However, there is no teaching concerning any synergistic effect of such combinations in the treatment of depression and/or anxiety. [0008] It has now been found that, surprisingly, therapeutic compositions comprising a combination of paroxetine or physiologically acceptable salts or solvates thereof, for administration in combination with 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro-pyrrolo[1,2- -a]-pyrazin-2-yl)-piperidine-1-carboxylic acid [-1-(R)-(3,5-bis-trifluoromethyl-phenyl)ethyl]-methylamide or pharmaceutically acceptable salts or solvates thereof to a human for the treatment of depression and/or anxiety, in which the dosage of the individual components are administered below the usual single therapeutic dosages, show surprising synergistic levels of efficacy for the treatment and/or prophylaxis of depression and/or anxiety. [0009] In particular, it has now been found that by combining a therapeutically non-effective dose of paroxetine or physiologically acceptable salts or solvates thereof, and a therapeutically non-effective dose of 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro-pyr- rolo[1,2-a]-pyrazin-2-yl)-piperidine-1-carboxylic acid [-1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide or pharmaceutically acceptable salts or solvates thereof a significantly greater antidepressant activity and/or anxiolytic activity than either of the two individual components taken alone is achieved. [0010] It is a feature of this invention that the use of such a combination will provide one or more of the following effects: a more efficacious anti-depressive and/or anti-anxiety drug and/or a better tolerated drug treatment and/or a drug with a more rapid onset of the anti-depressive and/or anti-anxiety activity. [0011] Furthermore, the synergistic effect of the combination of the present invention allows better management of any potential drug-related side effects. [0012] According to one aspect of the invention, there is provided a combination comprising a therapeutically non-effective dose of paroxetine or physiologically acceptable salts or solvates thereof, and a therapeutically non-effective dose of 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S-((8aS)-6-oxo-hexahydro-pyrrolo[1,2-- a]-pyrazin-2-yl)piperidine-1-carboxylic acid [-1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide or pharmaceutically acceptable salts or solvates thereof. [0013] When used in any of the contexts or aspects of the present invention a therapeutically non-effective dose refers to a dosage of each component of the combination which is lower than normally expected to produce effective therapeutic response when each component is administered alone. [0014] When used in any of the contexts or aspects of the present invention, paroxetine or physiologically acceptable salts or solvates thereof, may be administered as the free base, or in the form of any physiologically acceptable salt thereof, including all hydrated or anhydrous forms and all polymorphic forms of such salts. In particular, references to paroxetine or physiologically acceptable salts or solvates thereof, include, without limitation, paroxetine hydrochloride, paroxetine hydrochloride hemihydrate, paroxetine hydrochloride anhydrate, paroxetine mesylate and all polymorphic forms thereof. [0015] Paroxetine is preferably used in the form of its hydrochloride hemihydrate salt. [0016] Suitable pharmaceutically acceptable salts of 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro-pyrrolo[1,2- -a]-pyrazin-2-yl)-piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide include acid addition salts formed with pharmaceutically acceptable organic or inorganic acids, for example hydrochlorides, hydrobromides, sulphates, alkyl- or arylsulphonates (e.g. methanesulphonates or p-toluenesulphonates), phosphates, acetates, citrates, succinates, tartrates, fumarates and maleates. [0017] Preferred physiologically acceptable salts of 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro-pyrrolo[1,2- -a]-pyrazin-2-yl)-piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide include hydrochloride, methanesulphonate, sulphate, p-toluensulphonate. [0018] 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)((8aS)-6-oxo-hexahydro-pyrrol- o[1,2-a]-pyrazin-2-yl)-piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide is preferably used in the form of its hydrochloride salt. [0019] According to the invention a therapeutically non-effective dose of 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro-pyrrolo[1,2- -a]-pyrazin-2-yl)-piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide or pharmaceutically acceptable salts or solvates thereof, may be in the range of 0.25 to 1 mg per day (measured as the free base) preferably in the range of 0.5 to 1 mg per day. [0020] According to the invention a therapeutically non-effective dose of paroxetine or physiologically acceptable salts or solvates thereof ( measured as the free base) may be in the range of 1 to 10 mg per day, preferably in the range of 3.5 to 7.5 mg per day. [0021] A combination according to the invention conveniently comprises paroxetine or physiologically acceptable salts or solvates thereof, (measured as the free base) in an amount from 1 mg to 10 mg, more particularly in an amount from 3.5 mg to 7.5 mg, and 2-(R)-(4-Fluoro-2-methyl-phenyl) (S-((8aS)-6-oxo-hexahydro-pyrrolo[1,2-a]-pyrazin-2-yl)-piperidine-1-carbo- xylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide or pharmaceutically acceptable salts or solvates thereof, in an amount from 0.25 mg to 1 mg (measured as the free base) and particularly in an amount from 0.5 mg to 1 mg [0022] A preferred combination according to the invention comprises paroxetine or physiologically acceptable salts or solvates thereof, in an amount from 1 to 10 mg (measured as the free base) and 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro-pyrrolo[1,2- -a]-pyrazin-2-yl)-piperidine-1-carboxylic acid [-1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide or pharmaceutically acceptable salts or solvates thereof, in an amount from 0.25 to 1 mg (measured as the free base). [0023] A preferred combination according to the invention comprises paroxetine or physiologically acceptable salts or solvates thereof, in an amount from 1 to 10 mg (measured as the free base) and 2-(R)-(4Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro-pyrrolo[1,2-- a]-pyrazin-2-yl)-piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide or pharmaceutically acceptable salts or solvates thereof, in an amount from 0.5 to 1 mg (measured as the free base). [0024] A preferred combination according to the Invention comprises paroxetine or physiologically acceptable salts or solvates thereof, in an amount from 3.5 to 7.5 mg (measured as the free base) and 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro-pyrrolo[1,2- -a]-pyrazin-2-yl)-piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide or pharmaceutically acceptable salts or solvates thereof, in an amount from 0.25 to 1 mg (measured as the free base). 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